Atherosclerosis is a process by which new lesions can progress or become vulnerable from pre-existing ones, and can be summarised as the culmination of i) increased endothelial cell dysfonction; ii) migration of inflammatory cells into extracellular matrix; iii) synthesis and release of degrading matrix molecules; iv) fibrous cap thinning, erosion and/or rupture; v) release of growth factors; vi) prothrombotic, proinflammatory, proapoptotic and/or proatherosclerotic status. Physiological vascular healing and regeneration are highly coordinated processes that occur in individuals under specific conditions, such as during spontaneous plaque rupture and/or destabilisation, or induced by percutaneous or surgical revascularization.
Estrogens play an important role in bone maintenance, in the cardiovascular system, in the growth, differentiation and biological activity of various tissues1. The protective effects of 17-beta-estradiol (17βE) are related to favourable changes in plasma lipid profile2, to inhibition of vascular smooth muscle cell (VSMC) proliferation3 and migration4, to relaxation of coronary vessels through endothelial nitric oxide synthase (eNOS) activity5, to reduction of platelets and monocyte aggregation6, tumor necrosis factor alpha (TNF-a) release7 and extracellular matrix synthesis8. We have shown that local delivery of 17βE reduces neointimal thickness after coronary balloon injury in a porcine model8.
Estrogen can bind to two estrogen receptors (ER), alpha (ERα) and beta (ERβ), which are expressed in all vascular cells types10. The classical genomic mechanism, or long-term effect of estrogen on vascular tissues, is dependent on change in gene expression in the vascular tissues. Most recently, a second mechanism with direct (or nongenomic) estrogen effect has been identified11. Administration of estrogen can induce a rapid effect suggesting that its activities are linked to the induction of other intracellular pathways such as the mitogen-activated protein kinases (MAPKs)11. The MAPKs, which are involved in the proliferation, migration and differentiation of VSMC, are stimulated in rat carotid arteries after endothelial injury12. Treatment with estrogen may influence the MAPK pathway in a variety of cell types and may provide protection against vascular injury.
As indicated above, the major effects of estrogens are mediated through the two distinct estrogen receptors, ERα and ERβ. Each of these ER is encoded by a unique gene19 with some degree of homology between each other, and the genes are organized into six domains (A to F)10. The amino-terminal A-B domain represents the ligand-independent transcriptional-activation function 1 (TAF-1). The ER have only 18% of homology in this amino-terminus domain. The C domain, which represents the DNA binding domain, is extremely conserved in all steroid receptors and domain D contains the hinge region of the ER. The hormones bind the E domain which also contains a ligand-dependent transcriptional-activation function 2 (TAF-2). The two ER have 97% and 60% homology in domains C and E, respectively. The carboxy-terminal F domain is a variable region and it has been proposed that the F domain may play an important role in the different responses of ER to 17-beta-estradiol or selective ER modulators20. The expression pattern of the two ER are very different in many tissues and may suggest distinct responses in the presence of 17-beta-estradiol. Three studies with transgenic knock-out (KO) mice were done and the treatment with 17-beta-estradiol, in the absence of one of two ER (αERKO and βERKO) or both ER (αβERKO) prevented the hyperplasia formation after carotid injury.